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NM_004959.5(NR5A1):c.841C>T (p.Arg281Cys) AND 46,XY sex reversal 3

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 10, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004555172.1

Allele description [Variation Report for NM_004959.5(NR5A1):c.841C>T (p.Arg281Cys)]

NM_004959.5(NR5A1):c.841C>T (p.Arg281Cys)

Gene:
NR5A1:nuclear receptor subfamily 5 group A member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q33.3
Genomic location:
Preferred name:
NM_004959.5(NR5A1):c.841C>T (p.Arg281Cys)
HGVS:
  • NC_000009.12:g.124500119G>A
  • NG_008176.1:g.12302C>T
  • NM_004959.5:c.841C>TMANE SELECT
  • NP_004950.2:p.Arg281Cys
  • NC_000009.11:g.127262398G>A
  • NM_004959.4:c.841C>T
Protein change:
R281C
Molecular consequence:
  • NM_004959.5:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
46,XY sex reversal 3
Synonyms:
SEX REVERSAL, XY, WITH OR WITHOUT ADRENAL FAILURE; 46,XY SEX REVERSAL, PARTIAL OR COMPLETE, NR5A1-RELATED; NR5A1-Related 46,XY CGD; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0013066; MedGen: C3489793; OMIM: 612965

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005044096New York Genome Center - PrenatalSEQ
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Pathogenic
(Nov 10, 2021) 		de novoclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center - PrenatalSEQ, SCV005044096.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The de novo c.841C>T (p.Arg281Cys) missense variant identified in exon 4 (of 7) of the NR5A1 gene has been reported as heterozygous in an adult individual with partially virilized 46, XY DSD [PMID: 31745530], and in an another unrelated adult individual with severe gonadal dysplasia [PMID: 33728612]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects a highly conserved residue (Arg281) located in the ligand-binding domain of the NR5A1 protein [PMID: 31745530] and is predicted deleterious by multiple in silico prediction tools (CADD score = 28.7, REVEL score = 0.855). A different missense variant (p.Arg281Pro) affecting the same p.Arg281 has been reported in a newborn with 46, XY DSD [PMID: 21163476]. In vitro functional analyses suggest that the c.841C>T (p.Arg281Cys) variant identified in this fetus as well as the c.842G>C (p.Arg281Pro) variant affecting the same Arg281 codon severely reduce the expression of downstream target genes [PMID: 33728612, 21163476]. Based on the available evidence, the c.841C>T (p.Arg281Cys) variant identified in the NR5A1 gene is reported as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 8, 2024